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Title 

Disruption of CR6-interacting factor-1 (CRIF1) in mouse islet beta cells leads to mitochondrial diabetes with progressive beta cell failure

Authors 

Y K KimK H JoungM J RyuS J KimH KimH K ChungM H LeeS E LeeM J ChoiJ Y ChangH J HongK S KimS H LeeG R KweonChul Ho LeeH J KimM Shong

Publisher 

Springer Verlag (Germany)

Issue Date 

2015

Citation 

Diabetologia, vol. 58, no. 4, pp. 771-780

Keywords 

Beta cell failureCRIF1Mitochondrial oxidative phosphorylation

Abstract 

Aim/hypothesis: Although mitochondrial oxidative phosphorylation (OxPhos) dysfunction is believed to be responsible for beta cell dysfunction in insulin resistance and mitochondrial diabetes, the mechanisms underlying progressive beta cell failure caused by defective mitochondrial OxPhos are largely unknown.Methods: We examined the in vivo phenotypes of beta cell dysfunction in beta cell-specific Crif1 (also known as Gadd45gip1)-deficient mice. CR6-interacting factor-1 (CRIF1) is a mitochondrial protein essential for the synthesis and formation of the OxPhos complex in the inner mitochondrial membrane.Results: Crif1beta?/? mice exhibited impaired glucose tolerance with defective insulin secretion as early as 4 weeks of age without defects in islet structure. At 11 weeks of age, Crif1beta?/? mice displayed characteristic ultrastructural mitochondrial abnormalities as well as severe glucose intolerance. Furthermore, islet area and insulin content was decreased by approximately 50% compared with wild-type mice. Treatment with the glucoregulatory drug exenatide, a glucagon-like peptide-1 (GLP-1) agonist, was not sufficient to preserve beta cell function in Crif1beta?/? mice.Conclusions/interpretation: Our results indicate that mitochondrial OxPhos dysfunction triggers progressive beta cell failure that is not halted by treatment with a GLP-1 agonist. The Crif1beta?/? mouse is a useful model for the study of beta cell failure caused by mitochondrial OxPhos dysfunction.

ISSN 

0012-186X

Link 

http://dx.doi.org/10.1007/s00125-015-3506-y

Appears in Collections

1. Journal Articles > Journal Articles

Registered Date

2019-05-02


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